Metabolic profile changes in the testes of mice with streptozotocin-induced type 1 diabetes mellitus.

Contrary to the traditional view, recent studies suggest that diabetes mellitus has an adverse influence on male reproductive function. Our aim was to determine the effect of diabetes on the testicular environment by identifying and then assessing perturbations in small molecule metabolites. Testes were obtained from control and streptozotocin-induced diabetic C57BL/6 mice, 2, 4 and 8 weeks post-treatment. Diabetic status was confirmed by glycated haemoglobin, non-fasting blood glucose, physiological condition and body weight. A novel extraction procedure was utilized to obtain protein free, low-molecular weight, water soluble extracts which were then assessed using (1)H nuclear magnetic resonance spectroscopy. Principal component analysis of the derived profiles was used to classify any variations, and specific metabolites were identified based on their spectral pattern. Characteristic metabolite profiles were identified for control and type 1 diabetic animals with the most distinctive being from mice with the largest physical deterioration and loss of body weight. Eight streptozotocin-treated animals did not develop diabetes and displayed profiles similar to controls. Diabetic mice had decreases in creatine, choline and carnitine and increases in lactate, alanine and myo-inositol. Betaine levels were found to be increased in the majority of diabetic mice but decreased in a few animals with severe loss of body weight and physical condition. The association between perturbations in a number of small molecule metabolites known to be influential in sperm function, with diabetic status and physiological condition, adds further impetus to the proposal that diabetes influences important spermatogenic pathways and mechanisms in a subtle and previously unrecognized manner.

Bradykinin, insulin, and glycemia responses to exercise performed above and below lactate threshold in individuals with type 2 diabetes.

The aim of this study was to analyze the acute responses of bradykinin, insulin, and glycemia to exercise performed above and below lactate threshold (LT) in individuals with type 2 diabetes mellitus (T2D). Eleven participants with a diagnosis of T2D randomly underwent three experimental sessions 72 h apart: 1) 20 min of exercise performed at 120% of LT (120%LT), 2) 20 min of exercise performed at 80% of LT (80%LT), and 3) 20 min of control session. Blood glucose was analyzed before, during, and at 45 min post-exercise. Bradykinin and insulin were analyzed before and at 45 min post-exercise. Both exercise sessions elicited a parallel decrease in glucose level during exercise (P≤0.002), with a greater decrease being observed for 120%LT (P=0.005). Glucose decreased 22.7 mg/dL (95%CI=10.3 to 35, P=0.001) at the 45 min post-exercise recovery period for 80%LT and decreased 31.2 mg/dL (95%CI=18.1 to 44.4, P<0.001) for 120%LT (P=0.004). Insulin decreased at post-exercise for 80%LT (P=0.001) and control (P≤0.035). Bradykinin increased at 45 min post-exercise only for 80%LT (P=0.013), but was unrelated to the decrease in glucose (r=-0.16, P=0.642). In conclusion, exercise performed above and below LT reduced glycemia independently of insulin, but exercise above LT was more effective in individuals with T2D. However, these changes were unrelated to the increase in circulating bradykinin.

Evaluation of Components of Fusarium Head Blight Resistance in Soft Red Winter Wheat Germ Plasm Using a Detached Leaf Assay.

A large environmental influence on phenotypic estimates of disease resistance and the complex polygenic nature of Fusarium head blight (FHB) resistance in wheat (Triticum aestivum) are impediments to developing resistant cultivars. The objective of this research was to investigate the utility of a detached leaf assay, inoculated using inoculum from isolates of Microdochium nivale var. majus, to identify components of FHB resistance among 30 entries of U.S. soft red winter wheat in the 2002 Uniform Southern FHB Nursery (USFHBN). Whole plant FHB resistance of the USFHBN entries was evaluated in replicated, mist-irrigated field trials at 10 locations in eight states during the 2001-2002 season. Incubation period (days from inoculation to the first appearance of a dull gray-green water-soaked lesion) was the only detached leaf variable significantly correlated across all FHB resistance parameters accounting for 45% of the variation in FHB incidence, 27% of FHB severity, 30% of Fusarium damaged kernels, and 26% of the variation in grain deoxynivalenol (DON) concentration. The results for incubation period contrasted with previous studies of moderately resistant European cultivars, in that longer incubation period was correlated with greater FHB susceptibility, but agreed with previous findings for the Chinese cultivar Sumai 3 and CIMMYT germ plasm containing diverse sources of FHB resistance. The results support the view that the detached leaf assay method has potential for use to distinguish between specific sources of FHB resistance when combined with data on FHB reaction and pedigree information. For example, entry 28, a di-haploid line from the cross between the moderately resistant U.S. cultivar Roane and the resistant Chinese line W14, exhibited detached leaf parameters that suggested a combination of both sources of FHB resistance. The USFHBN represents the combination of adapted and exotic germ plasm, but four moderately resistant U.S. commercial cultivars (Roane, McCormick, NC-Neuse, and Pat) had long incubation and latent periods and short lesion lengths in the detached leaf assay as observed in moderately FHB resistant European cultivars. The dichotomy in the relationship between incubation period and FHB resistance indicates that this may need to be considered to effectively combine exotic and existing/adapted sources of FHB resistance.

Clindamycin-induced colitis.

The hamster model of enterocolitis after the administration of clindamycin was used to study various drugs used in treatment of the disease in humans. Current evidence strongly suggests toxigenic, clindamycin-resistant Clostridium difficile is a cause of the disease in hamster and man. This organism is susceptible to vancomycin and metronidazole, and the disease could be prevented in the hamster so long as the antibiotics were given orally. A fatal colitis almost invariably ensued once they were discontinued. Administration of cholestyramine significantly prolonged survival of hamsters, but did not pervent death or colitis. Corticosteroids or atropine-diphenoxylate (Lomotil) did not alter the disease. The hamster model may be useful in studying other kinds of treatment of this disease.

Studies on the epidemiology of antibiotic-associated Clostridium difficile colitis.

Vancomycin protects hamsters from the development of Clostridium difficile colitis after treatment with clindamycin, and vancomycin is useful in treatment of humans with the disease. Relapses have occurred in both hamsters and humans when vancomycin is discontinued. Vancomycin appears to enhance susceptibility to colonization with C. difficile by eliminating competing intestinal organisms. The nature of these organisms is not known, but various tools are now available to aid in identifying them. Cancer chemotherapeutic agents should be added to the list of factors such as surgery and antibiotics that may predispose to emergence of C. difficile. The number of organisms required for colonization of antibiotic-treated hamsters is low and cross-infection seems to play a role in the disease in hamster colonies. The organism can be detected on surfaces in rooms of patients with the disease, and on the hands of personnel caring for them. Outbreaks of the disease have been recognized. Our results suggest isolation precautions should be used to prevent spread of the organism from patients with the disease to others being treated with antibiotics.

Designing naturalistic prospective studies of economic and effectiveness outcomes associated with novel antipsychotic therapies.

The cornerstone of recent pharmacoeconomic work in schizophrenia is the hypothesis that the improved efficacy of novel antipsychotic medications will lead to a reduction in medical services utilization, thereby reducing direct medical costs associated with treatment. Creating the most valid design to prospectively examine the effectiveness and costs of competing pharmacotherapies requires a dialectic of opposing research paradigms. The final protocol must represent a series of decisions that strike a careful balance between being scientifically sound (internal validity) and generalizable to the real world of clinical treatment (external validity). The results must be useful to decision-makers in determining to what extent reductions in healthcare expenditures can offset higher drug acquisition costs within their type of treatment environment. This article is a review of several methodological challenges in the design of medical effectiveness trials, including whether to blind the study, definition of the patient population, degree of physician discretion in treatment, and how to collect and analyze data for patients who discontinue their originally assigned medication. The article also provides a discussion of how clinical practices can inform decisions made to meet these challenges. The issues are illustrated through a prospective study designed to evaluate the cost-effectiveness of the newer antipsychotics in general and olanzapine in particular. Cost-effectiveness studies of novel antipsychotic medications, particularly those with naturalistic designs, will increase in importance as the use of these second-generation agents continues to expand.

Dialogue. Prescription for problems? Capitating mental health drugs--the great debate.

With the issue of physician capitation far from being resolved, mental health drug capitation is understandably up for debate. Those who deem it essential point to the rising cost of mental health drugs and urge management techniques which they believe can hold the delicate balance between a plan's budgetary limitations and a patient's appropriate care. They suggest that with an objectively calculated capitation rate, based not on expenditure alone, but on a defined population and their care needs, providers will not have to choose between profitability and optimal care. But others, responding to increasing quality concerns under capitation, worry that the increasing use of formularies will preclude patients and their providers from ready access to newer, more effective medications. With advocates still striving for nationwide parity for mental health benefits, capitating medications is not likely to assuage their concerns. Driving the debate is the fact that new technology drugs are expensive and most health plans are unable to anticipate the funding of breakthrough pharmaceuticals. With the advent of marketing to consumers directly through television and print media, plans and providers are increasingly pressured to provide these medications. The recent clamor for Viagra is an excellent example of how quickly the word can spread. New mental health medications may be even more expensive and offer patients and their families greater effectiveness with far fewer side effects. Plans, providers, and patients are caught in the middle, each holding their distinct view of the problems and solutions. This issue's dialogue brings our readers a discussion of capitation of pharmaceuticals as a primary answer to the sharp rise in mental health drugs. Three points of view lay out the viability and cautions of developing formularies and systems that could keep costs under control while still providing patient access. Without question, the debate will continue as legislative and consumer pressure continues to focus on managed care's techniques for cost savings and patient management. More sophisticated systems, designed for increasingly integrated and complex treatment plans, are certain to be required in the future. However, decisions about how to develop practice guidelines and integrate formularies with expensive new pharmaceutical technology, must begin to take shape now.

Implementation issues in disease management programs: a pharmaceutical company perspective.

Eli Lilly, a pharmaceutical manufacturer, recently established a disease management subsidiary. The author, one of the key forces behind the new venture, provides a how-to based on the company's experiences in developing Integrated Disease Management, Inc. His views, from the pharmaceutical company perspective, may also be applicable to any organization seeking to climb into the red-hot arena of disease management.

Population genetics and ecology of Artemia: Insights into parthenogenetic reproduction.

The relative advantages of sexual and parthenogenetic reproduction have long interested biologists and remain a central issue in ecological and evolutionary studies. Recent data on brine shrimp (Artemia) indicate that extensive ecological and genetic divergence occurs in an obligately parthenogenetic lineage. This challenges the belief that parthenogenetic lineages are evolutionary 'dead ends' and that extensive divergence is necessarily linked to recent recruitment from sexual ancestors. The molecular evidence suggests that parthenogenesis in Artemia is relatively ancient, with a single asexual lineage branching from an Old World sexual ancestor approximately five million years ago. Automictic recombination (which can occur in diploid but not polyploid parthenogenetic brine shrimp) appears to play a central role in the long-term maintenance of the parthenogenetic lineage.

Knotting of an epidural catheter: a case report.

Difficulty with removal of an epidural catheter is described due to formation of a knot near the end of the catheter. It is stressed that in the lumbar area an epidural catheter should never be inserted more than 5 cm into the epidural space, as curling with knot formation may occur. Removal may be attempted by pulling on the catheter if testing of a similar catheter indicates that it will withstand the tension. The patient and the spouse should be kept informed and involved in the decision-making for medico-legal reasons.

The use of intrathecal phenol for muscle spasms in multiple sclerosis. A description of two cases.

Two cases of multiple sclerosis are described, in both of whom the disease started in yound adult life. This disability gradually progressed to the stage of paraplegia-in-flexion in which the lower limbs were fixed in adduction-and-flexion. Both patients developed painful muscle spasms which made life intolerable. These patients were treated by intrathecal phenol in glycerine in an effort to convert this spastic paralysis into a flaccid paralysis. The three advantages sought were: 1. To relieve the muscle spasms so that the patient could sit in a wheelchair and propel herself. 2. To relieve the pain of the spasms. 3. To allow access to the perineum for proper hygienic care of bladder and bowel function. The first patient obtained an excellent result (Figures 1, 2, 3) but blocks had to be repeated after approximately five months. The second patient after the block developed a good result in the right leg, but still had mild, but painless spasms in the muscles of the left leg (Figures 4 and 5). However, she was able to use a wheelchair and was discharged to a chronic hospital where she died of bulbar paralysis six months later. Intrathecal phenol thus appears to be a useful method for relieving muscle spasms and pain in the lower extremities in advanced cases of multiple sclerosis.

Infectious diseases and the anaesthetist.

The methods of dealing with various items of anaesthetic equipment in order to assure a fresh supply for each patient have been discussed. These consist of using disposable items, steam sterilization, disinfection by both chemical methods and pasteurization and the use of ethylene oxide sterilization. The use of disposable bacterial and viral filtres to protect ventilators and soda lime cannisters is discussed. These can then be sterilized by ethylene oxide at less frequent intervals, i.e., weekly. Protection of the anaesthetists' skin from contact with body fluids by the use of barrier methods are stressed. Methods to avoid penetration of the skin by needlestick and sharp objects are discussed. The increasing number of persons being treated for opportunistic infections makes it likely that anaesthetists will encounter increasing numbers of patients infected with HIV. The more common infections encountered in the operating room in North America have been included, with methods of avoiding possible infection from them. Constant vigilance and the use of universal precautions when caring for all patients is therefore required by the anaesthetist in the operating room in order to avoid contacting infection from patients.

Viral hepatitis and the anaesthetist.

Viral hepatitis is a constant hazard to all operating room personnel. The anaesthetist should avoid contact with patients' blood and saliva as much as is possible. Hepatitis A (HAV) is spread mainly by faecal/oral contact. Carriers are almost non-existent in this disease and the main importance to the anaesthetist is that he may contact a patient who is acutely infected or one who is incubating HAV. Diagnosis of postoperative hepatic dysfunction may then be a problem. Prophylaxis with Gamma globulin is also stressed. Hepatitis B (HBV) and Non-A Non-B hepatitis (NANB) have a high incidence of carriage, and are spread mainly by blood contact. The groups of patients whom the anaesthetist should especially be aware of are reviewed, as is prophylaxis using Hepatitis B Immune Globulin and the recently introduced Hepatitis B vaccine. NANB continues to be a diagnostic problem, its diagnosis being mainly by exclusion of other causes of viral hepatitis. It appears to be responsible for more than 90 per cent of cases of posttransfusion hepatitis and more than one virus may be involved.

Hepatitis B virus antibody prevalence in anaesthetists.

The prevalence of antibodies to hepatitis B virus (anti HBs or anti HBc) was 16.9 per cent in a group of anaesthetists, compared to 3.7 per cent in volunteer blood donors and 5.6 per cent of patients without hepatic infections. Professional risk factors such as treating a hepatitis B patient or working in a hospital laboratory, haemodialysis, an intensive care unit, or in oncology, did not correlate with antibody prevalence. Personal risk factors such as a history of a family member with hepatitis, or of receiving blood transfusion in the past were also not associated. A greater number of anaesthetists with a history of hepatitis in the past had antibodies, than those with no history (p less than 0.05). The country of origin may have been a contributing factor to antibody prevalence as highest positivity rates were found in subjects from Asia, Africa and Eastern Europe. One of 31 (3.2 per cent) seronegative subjects seroconverted over a four-year period. Results of testing in 1978 and 1982 revealed that 37 per cent of immune subjects possessed only anti HBc and at least one person positive for both markers on the first occasion was only anti HBc positive later. Laboratory testing, risk factors, and immunization for HBV should be examined in greater detail in larger populations of health care workers.

Variation in the disposition of morphine after i.m. administration in surgical patients.

The disposition of morphine when administered by i.m. injection was studied in 36 patients receiving morphine as part of premedication before general anaesthesia, and in five patients who received morphine as a postoperative analgesic after median sternotomy for coronary artery surgery (PCA group). Maximum plasma concentration of morphine (CP max) was 75.3 +/- 6.0 (mean elimination rate constant (k) 4.85 X 10(-3) min-1 and half-life (T1/2) = 143 min for the preanaesthetic group. The corresponding values for PCA group were CPmax = 58.0 +/- 18.0 ng ml-1 (range 30--130 ng ml-1), k = 5.63 X 10(-3) min-1 and T 1/2 = 123 min. Analysis of variance showed no differences between the groups. Within the preanaesthetic group, there was a significant difference in k between males (k = 4.01 X 10(-3) min-1) and females (6.30 X 10(-3) min-1, P less than 0.01). The corresponding T 1/2 for males was 173 min; and 110 min for females. The variation in the disposition of morphine is thought to be the result of variations in resting muscle blood flow and inadvertent injection into adipose tissue. There were no significant differences between males and females in the preanaesthetic group with respect to age, Cpmax or time from injection to Cpmax.

Clindamycin-induced enterocolitis in hamsters.

A lethal enterocolitis was induced in hamsters by oral or parenteral administration of clindamycin in amounts comparable to those used in treatment of humans. The intestinal lesions were characterized histologically as an acute inflammatory reaction with pseudomembrane formation and resembled the lesions seen in humans with antibiotic-induced colitis. Results of quantitative stool cultures showed the numbers of Peptostreptococcus and Corynebacterium decreased in animals with colitis after challenge with 100 mg of clindamycin/kg, while numbers of Escherichia coli, Streptococcus faecalis, and clindamycin-resistant Clostridium sordellii and Clostridium difficile increased. Bacteria were not seen within the intestinal lesions. Viruses were not isolated from hamsters with colitis. Although the pathogenesis of this syndrome is not completely established, the evidence is consistent with the hypothesis that the disease is caused by clostridial toxins and that the production of these toxins by organisms within the intestines is enhanced by the effects of clindamycin upon the bowel flora.

Right to left shunt measurement in patients suspect for pulmonary embolism.

31 patients suspect for acute pulmonary emboli were studied by measuring arterial PO2 (room air) and right to left shunt (100% oxygen breathing) to determine if measurement of the right to left shunt aided in the diagnosis of pulmonary embolism. Ventilation/perfusion or serial perfusion lung scans were performed on each patient. All patients exhibited arterial hypoxemia (PaO2 less than or equal to 80) and 27 had a shunt greater than 7%. The shunt was 15.1 +/- 3.6% in 9 patients with lung scans highly suggestive of emboli. 20 patients with lung scans of low probability for emboli had significantly less shunting averaging 10.9 +/- 3.7%. 5 patients of the latter group had shunts averaging 15.2 +/- 3.8% attributable to occult pneumonia not initially apparent. An increased right to left shunt fraction is not diagnostic of pulmonary emboli, but a normal one makes the diagnosis unlikely.